Parasites as causative agents of human affective disorders? The impact of anti-psychotic, mood-stabilizer and anti-parasite medication on Toxoplasma gondii's ability to alter host behaviour

Abstract

With increasing pressure to understand transmissible agents, renewed recognition of infectious causation of both acute and chronic diseases is occurring. Epidemiological and neuropathological studies indicate that some cases of schizophrenia may be associated with environmental factors, such as exposure to the ubiquitous protozoan Toxoplasma gondii. Reasons for this include T. gondii's ability to establish persistent infection within the central nervous system, its ability to manipulate intermediate host behaviour, the occurrence of neurological and psychiatric symptoms in some infected individuals, and an association between infection with increased incidence of schizophrenia. Moreover, several of the medications used to treat schizophrenia and other psychiatric disease have recently been demonstrated in vitro to possess anti-parasitic, and in particular anti-T. gondii, properties. Our aim here was thus to test the hypothesis that the anti-psychotic and mood stabilizing activity of some medications may be achieved, or at least augmented, through their in vivo inhibition of T. gondii replication and invasion in infected individuals. In particular we predicted, using the epidemiologically and clinically applicable rat-T. gondii model system, and following a previously described and neurologically characterized 'feline attraction' protocol that haloperidol (an anti-psychotic used in the treatment of mental illnesses including schizophrenia) and/or valproic acid (a mood stabilizer used in the treatment of mental illnesses including schizophrenia), would be, at least, as effective in preventing the development of T. gondii-associated behavioural and cognitive alterations as the standard anti-T. gondii chemotherapeutics pyrimethamine with Dapsone. We demonstrate that, while T. gondii appears to alter the rats' perception of predation risk turning their innate aversion into a 'suicidal' feline attraction, anti-psychotic drugs prove as efficient as anti-T. gondii drugs in preventing such behavioural alterations. Our results have important implications regarding the aetiology and treatment of such disorders.

Figure 1

Schematic diagram of 1×1 m test pen.

Figure 2

Impact of T. gondii and drug treatments on (a) feline attraction (measured here as duration spent in cat-scented areas) and (b) activity and behaviour. The ‘untreated’ comparison demonstrates the effect of untreated infection (specifically comparing untreated infected rats with untreated uninfected rats). The ‘HAL’, ‘PD’, and ‘VAL’ comparisons demonstrate the effect of drug treatment on infected rats (specifically comparing treated infected rats with untreated infected rats). An apparent suicidal feline attraction and risk behavioural profile was clearly associated with untreated infection. Behavioural traits likely to increase feline predation rate, and hence completion of the parasites life cycle, were all increased relative to their untreated uninfected counterparts. These included: an increased proportion of time spent in areas with evidence of cat presence (entrances and duration of time spent in cat areas); conspicuousness (still for greater than or equal to 3 s, while exposed, or increased activity, either measured as proportion of time spent ‘out’ versus inside a nest-box, or ‘active’ versus inactive, when a rat has already been within a nest-box for greater than 5 min with no nose poking out/movement inside the nest-box); and decreased attention on predator avoidance (grooming in exposed areas). Treatment of infected rats with both the anti-T. gondii PD and the anti-psychotic HAL reduced feline attraction, and reduced several predation-risk behavioural traits, with a similar non-significant trend for the mood-stabilizer VAL.